These magnetic resonance images of a child with radiation necrosis show the typical “Swiss cheese” or “soap bubble” enhancement pattern of necrotic lesions.

Treatments May Alleviate and Reverse Central Nervous System Radiation Necrosis

By Jill Delsigne

Although radiation therapy is effective against many tumors of the brain and spine, it also damages normal tissue.

One of the most debilitating types of damage is radiation necrosis of
the central nervous system (CNS). But in recent years, treatments have
been found that can slow—and in some cases reverse—this damage.

CNS radiation necrosis may cause any of the following symptoms:
abnormal headaches, seizures, personality changes, difficulty
concentrating or reading, a sense of slowing down, focal weakness, or
problems with speech. These symptoms can appear during or just after
radiation therapy (acute injury), within a few weeks or months after
treatment (early delayed injury), or 6 months to many years after
treatment (late radiation injury). Acute and early delayed injuries can
usually be reversed with steroid therapy, and sometimes they appear to
spontaneously resolve. Late radiation injury is the most serious kind
of damage and usually is irreversible.

Prevalence and causes

A retrospective study from The University of Texas MD Anderson Cancer
Center found that CNS radiation necrosis developed in 36 (24%) of 148
patients treated with radiation and chemotherapy after surgical
resection of glial tumors; of those patients, 16 (44%) had both
necrotic lesions and recurrent or residual tumors. Several studies have
shown that combining radiation therapy and chemotherapy increases the
incidence of brain necrosis to three times that seen with radiation
therapy alone. This combination disrupts the blood-brain barrier, which
allows chemotherapy to more effectively target tumor cells;
unfortunately, this disruption of the blood-brain barrier also makes
normal brain tissue vulnerable to damage.

“[T]he fact that even short treatment with bevacizumab seems to turn off the cycle of radiation damage further confirms the central role of VEGF in the process.”

– Dr. Victor Levin

Even though radiation necrosis was first reported more than 60 years
ago, potential mechanisms for this condition have only recently been
discovered. It has been shown that CNS radiation necrosis is associated
with increased cytokine production. According to this model, radiation
therapy causes vascular abnormalities in the brain that reduce blood
vessel density, ultimately restricting the blood supply to brain tissue
(chronic ischemia). Ischemia, in turn, causes infiltrative tumor cells
and adjacent astrocytes to respond by producing cytokines, such as
vascular endothelial growth factor (VEGF), to help the tumor cells or
astrocytes survive. In addition to irradiation, some chemotherapy drugs
also cause ischemia and may exacerbate necrosis.

Irradiation of the CNS can also produce damage to the myelin sheath of
neurons (demyelination). This appears to be caused by the effect of
radiation on the oligodendrocytes that make and repair the myelin
covering neuronal axons. This effect is seen early on magnetic
resonance images of most patients treated with radiation therapy, with
or without chemotherapy.

Diagnosis

CNS radiation necrosis is difficult to diagnose accurately because it
often appears the same as a progressive tumor on diagnostic imaging.
Radiation necrosis usually occurs at the treatment site but can also be
distant, usually near a cerebral ventricle; necrosis can also be
diffuse or multifocal and resemble tumor metastasis.

Ashok J. Kumar, M.D., a professor in the Department of Diagnostic
Radiology at MD Anderson, was the first author of a seminal study
published in 2000 of imaging patterns that differentiate radiation
necrosis from brain tumors. According to Dr. Kumar, diagnosing
radiation necrosis remains difficult, but experienced physicians can
recognize the patterns of necrosis and treat it early. Dr. Kumar said
radiation necrosis lesions have a “Swiss cheese” or “soap bubble”
enhancement pattern on magnetic resonance imaging (MRI). However, this
pattern does not provide a definitive diagnosis.

On diffusion-weighted MRI, which measures the magnitude and direction
of free water movement, tumors tend to restrict water movement, whereas
necrosis tends to increase water mobility. On magnetic resonance
spectroscopy, necrotic lesions tend to exhibit reduced levels of
N-acetyl aspartate and creatine, whereas tumors tend to exhibit high
levels of choline. Magnetic resonance perfusion, which measures the
relative cerebral blood volume, can indicate necrotic lesions, but this
modality also detects fast-growing tumors that exceed their blood
supply.

None of these imaging modalities can differentiate necrosis from tumor
progression (or necrotic lesions mixed with a recurrent tumor)
definitively. Even invasive tests such as biopsy cannot definitively
distinguish between necrosis and recurrent cancer owing to sampling
error. Experienced physicians and radiologists can learn to recognize
signs that indicate a high probability of necrosis versus tumor
progression. A diagnosis of CNS radiation necrosis instead of cancer is
not cause for relief, however. Necrosis can have the same debilitating
effects as a tumor and can even be fatal if unchecked.

Treatment

Until just a few years ago, treatment for CNS radiation necrosis was
restricted to alleviating its symptoms. Physicians have long prescribed
corticosteroids to control swelling and psychostimulants to address
psychomotor slowing and fatigue in patients with CNS necrosis.
Corticosteroids also help counteract the radiation-induced vascular
damage that can disrupt the blood-brain barrier. Sometimes symptoms
return if patients stop using the steroids, so problems arising from
chronic steroid use must also be treated. Anticoagulants, such as
warfarin or heparin, can slow the progression of necrosis in some
patients. Hyperbaric oxygen treatment can help restore oxygen
concentrations to a normal level in order to encourage angiogenesis.
Patients can also undergo brain surgery to remove necrotic tissue.

In 2009, a group at MD Anderson revolutionized treatment options for
radiation necrosis. They found that bevacizumab, a monoclonal antibody
that prevents blood vessel growth in tumors by blocking VEGF, also
causes necrotic lesions in the brain to regress, reversing radiation
damage. This observation spurred the design of a double-blind,
placebo-controlled phase II trial of bevacizumab as a therapy for CNS
radiation necrosis. Treatment involved four cycles of bevacizumab (7.5
mg/kg intravenously every 3 weeks). At a median 10 months’ follow-up, 9
of the 12 patients treated with the drug had necrotic lesion shrinkage
on MRI. This trial provided class I evidence of the efficacy of
bevacizumab as a treatment for CNS radiation necrosis.

“Just the fact that bevacizumab works has helped us understand much
more about what happens in radiation necrosis,” said Victor A. Levin,
M.D., a professor emeritus in the Department of Neuro-Oncology at MD
Anderson and the senior researcher on these studies. “We presume
necrosis is related to the release of cytokines like VEGF, since
bevacizumab is very specific and only reduces VEGF levels. We think
aberrant production of VEGF is involved with radiation necrosis of the
brain, and the fact that even short treatment with bevacizumab seems to
turn off the cycle of radiation damage further confirms the central
role of VEGF in the process.” Astrocytes try to protect neurons by
expressing VEGF, but this strategy threatens the brain by causing a
leak in the blood-brain barrier. Bevacizumab turns off this cytokine
loop and reduces plasma leakage across brain capillaries, thus reducing
brain edema.

MD Anderson researchers presented at the Society for Neuro-Oncology
conference in November 2011 on the ability of diffusion-weighted MRI to
predict which patients are most likely to benefit from bevacizumab
treatment.

Although some researchers have claimed that a larger study is needed to
validate bevacizumab as a standard treatment for CNS necrosis, Dr.
Levin asserts that the success of each treatment outside of a research
study adds to the growing evidence of its efficacy. He currently treats
primary brain tumor patients as part of the Kaiser Medical Group in
California and continues to prescribe bevacizumab, both pre-emptively
to minimize radiation damage and after treatment to reverse radiation
necrosis.

While research for treatments continues, advances in radiation therapy
may reduce the incidence and severity of CNS necrosis and other side
effects by minimizing radiation damage to healthy tissue. Dr. Levin
said that proton therapy may prove to be such an advance because
radiologists can calculate the trajectory of the proton to pinpoint the
release of energy to occur precisely when the proton reaches the tumor
cell, minimizing damage to the surrounding healthy tissue. Although
this new technique also has caused instances of radiation necrosis, Dr.
Levin is hopeful that it will lead to fewer cases of radiation necrosis
compared with other treatment modalities.